Understanding changes in cerebral and cerebellar motor representation during long-term motor training might help to develop most effective training procedures. For brain damage after stroke, these neuroplastic processes are different than those observed in healthy volunteers. Several factors modify training progress and motor representation in these patients. This talk will summarize recent findings on these issues and will focus predominantly on upper limb motor training. [mehr]

Recovery from spinal cord injury – and its attendant neurodegenerative processes – can follow a complicated trajectory spanning several years after trauma, where the ensuing diaschisis (meaning "shocked throughout") affects the entire neuroaxis. With potential treatments targeting repair of the injured spinal cord, there is an imperative to improve clinical trial design and efficiency, optimise patient stratification in the context of disease heterogeneity and identify potential trial outcome measures. The ability to track trauma-induced structural changes across the neuroaxis provides the opportunity to quantify pathological processes driving diaschisis and recovery-related plasticity. During my talk I will present evidence of progressive volume and microstructural changes (myelin and iron content) following acute spinal cord injury using state-of-the-art computational anatomy and post-processing tools. Further I will show latest developments of high-resolution MRI sequences and optimized post-processing methods to assess at the voxel level spinal cord grey and white matter changes. Finally, I will outline an integrative framework, which attempts to identify subgroups of neurologic disorders beyond standard clinical phenotyping – and to improve functional outcome with individualized treatment (i.e., precision neurology). This framework, franchised under the term “Embodied Neurology”, pays special emphasis on the reciprocal information flow between the body, spinal cord and brain. Spinal cord injury is a particularly interesting model in the context of EN as a focal traumatic lesion in the spinal cord has far reaching consequences in terms of both cortical reorganization at distant sites (cf. functional diaschisis) and the functional architecture within and beyond the spinal cord (cf. structural diaschisis). To establish EN there is a pressing need for further developments in neuroimaging with the aim to unify structural and functional biophysical models in order to link pathology to phenomenology with greater precision. [mehr]

The efficacy of various neurotransmitter systems declines with advancing age. Of particular interest, various pre- and post-synaptic components of the frontal and striatal dopaminergic systems show substantial negative age-related differences across the adult life span. Furthermore, anatomical and functional changes in the frontal and hippocampal regions are also hallmarks of brain aging. This talk will selectively highlight findings from recent neuroimaging, pharmacological and genetic studies about aging of the frontal-hippocampal-striatal circuitry and the implications for memory, spatial learning, and sequential decision-making in old age. [mehr]

In Clinical Neurology, ataxia denotes a syndrome of motor incoordination that typically results from dysfunction of the cerebellum and its afferent and efferent connections. Ataxia is also used to denote a group of neurodegenerative diseases of the cerebellum and its connections that are clinically characterized by progressive motor incoordination. Many of the ataxias have genetic causes, but there are also sporadic degenerative ataxias and ataxias which are due to acquired non-genetic causes. Overall, there is an enormous degree of heterogeneity among the ataxias with an estimated number of more than 150 different, molecularly defined diseases. Our research is focusing on the common, autosomal dominantly inherited spinocerebellar ataxias (SCA) which are caused by translated CAG repeat expansion mutations that code for an elongated polyglutamine tract within the respective proteins. To define the phenotype and natural history of these disorders we recruited a cohort of more than 500 patients and followed them over more than 8 years. Multivariate models allowed to explain up to 60% of the variability of the ataxia severity at baseline. Modelling of disease progression revealed genotype-specific patterns and identified biological factors that determine the rate of progression. MRI studies showed progressive grey and white matter tissue loss in cerebellum, brainstem and basal ganglia. Studies of a cohort of more than 300 apparently healthy SCA mutation carriers showed that first signs of impaired coordination and tissue loss of the brainstem or cerebellum occur more than 10 years before the clinical onset of ataxia. These observation led to a refined disease model of ataxia disorders that considers ataxia as a late disease stage which is preceded by extended asymptomatic and preclinical disease stages that offer a time window for early therapeutic intervention. Although CAG repeat expansion mutations are now known for more than two decades the mechanism how these mutations cause neurodegeneration remain far from clear. There is one component which is due to the toxic properties of proteins or protein fragments that contain elongated polyglutamine tracts. However, there are additional components that depend on the protein context of the polyglutamine tract and are disease specific. Currently, there is no treatment for SCA. Experimental work in cells and animals aims to reduce levels of mutant proteins using RNA interference (RNAi)and antisense oligonucleotides (AONs). An alternative approach is protein modification through AON-mediated exon skipping. As there are many obstacles to translate these approaches into clinical application there is renewed interest in finding drugs that interfere with cerebellar neuronal activity and thereby symptomatically improve ataxia. [mehr]

Human decision making often involves weighting of values obtained via the rewarding quality of experience, but can uniquely incorporate more abstract aspects such as information about possible long-term consequences. While the former is computationally simple and efficient, the latter requires utilization of a model about the world. I will present results of two studies aiming to disentangle unique learning mechanisms for both propensities. The first will focus on the cortical temporal dynamics of learning from reward compared to information revealed in the human EEG. The second will focus on regional specificity of neural correlates of learning from model-free and model-based outcomes that dissociate ventral from dorsal striatum in the fMRI. [mehr]

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We all have our habits, good and bad. But only for some, habits go from bad to worse and behaviour becomes compulsive, as we see for example in addiction or clinical overeating. How is it that a useful mechanism such as our habit system can come to work against us? Why does it happen for only some and not others when faced with tempting rewards? And how can we get back in control? In my doctoral studies I aimed to increase our understanding of this by investigating the neural and cognitive mechanisms underlying compulsive gambling (in gambling addiction) and eating behaviour (in a non-clinical population). Building on an extensive body of addiction literature, I used a variety of experimental paradigms to tap into different aspects of compulsive behaviour. I focussed in particular on altered reward processing and loss of control over automatic tendencies triggered by reward-related stimuli. Furthermore, I investigated the effects of a pharmacological (dopamine) and a behavioural (mindfulness) intervention on reward processing. [mehr]

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Responding to stress is adaptive for most complex organisms, aiding survival by temporarily mobilizing resources to let the organism better flee or defend itself in response to a perceived threat. Once the threat is ended, the response normally subsides, allowing the organism to pursue other key survival activities. But if the stress response never reverses, or is triggered inappropriately, as with extreme stressors such as trauma, it may lead to psychiatric disorders such as anxiety and PTSD. Some individuals, like Special Forces soldiers, are inherently resilient to most stressors. Such resilient individuals have higher levels of Neuropeptide Y (NPY) in their blood and CSF. Experimental injections of NPY into brain ventricles or into the amygdala of rodents can induce an acute resilience to stress and a prolonged (weeks to months) period of resilience with just a few repeated treatments. Conversely, the stress hormone, Corticotrophin Releasing Factor (CRF), respectively causes acute and prolonged vulnerability to stress when injected acutely or repeatedly into the same brain structures. Activity of projection neurons (PNs) in the basolateral amygdala (BLA) mediates fear and anxiety responses, and reducing PN activity reduces both. Earlier work from the Colmers and Urban laboratories demonstrated opposing actions of NPY and CRF on BLA PN excitability: NPY acutely hyperpolarized these cells, while CRF acutely depolarized them. The mechanism was unusual, in that NPY reduced a membrane ion current, the H-current (Ih), while CRF activated it. Because Ih is hyperpolarization-activated, it is active at the resting potential, so by closing Ih, NPY hyperpolarizes PNs, while CRF opening it depolarizes them. Repeated (5 x daily) injection of NPY causes stress resilience in rats (seen as increased social interaction) persisting longer than 4 weeks. BLA PNs from NPY-treated animals were hyperpolarized at 4W, exhibiting a relative marked loss of Ih and correlating with reductions in mRNA and protein levels for HCN1, the Ih channel subunit in these cells. shRNA knockdown of HCN1 in BLA caused long-term behavioral stress resilience, indicating HCN1’s role in behavior. Using a novel organotypic slice culture system of the BLA, we studied mechanisms underlying long-term changes, mimicking the repeated application of NPY and receptor-selective agonists. Briefly, NPY did reduce Ih in these cells,but more prominently reduced the extent of BLA PN dcendrites, while CRF increased them (as is known to happen in vivo both with CRF and stress). Studies in BLA from NPY-treated rats confirmed the reduction in dendritic trees in vivo. The NPY Y5 receptor mediates the long-term changes, and requires calcineurin and the autophagic pathway to do so, while the CRFR1 receptor is involved in the increase, and requires CaMKII. Because the work wasa all done in male rats, ongoing work is determining if the same actions of NPY and CRF occur in female BLA. [mehr]

Interacting with an individual brain in closed loop can open the door for detailed introspection into sensorimotor and cognitive processes. However, closed-loop paradigms require data analysis methods capable of decoding neural components of interest in single-trial, despite of low signal-to-noise ratio and non-stationarity. In my talk, I will report on two novel algorithmic developments of my lab. The methods allow for the robust supervised regression of informative oscillatory components of the EEG and the unsupervised classification of evoked potentials. Then I will show, how the derived components can be exploited in two brain state informed stroke therapy paradigms, which are designed to train up (1) hand motor performance and (2) the language network of chronic aphasic patients after stroke. [mehr]

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Many eating-related psychological constructs have been proposed to explain obesity and over-eating. However, these constructs, including food addiction, disinhibition, hedonic hunger, emotional eating, binge eating, and the like all have similar definitions, emphasising loss of control over intake. As questionnaires measuring the constructs correlate strongly (r>0.5) with each other, we propose that these constructs should be reconsidered to be part of a single broad phenotype: Uncontrolled Eating (UE). Such an approach enables reviewing and meta-analysing evidence obtained with each individual questionnaire. Here, we describe robust associations between UE, body mass index (BMI), food intake, psychological traits, and brain systems. Reviewing cross-sectional and longitudinal data, we show that UE is phenotypically and genetically intertwined with BMI and food intake. We also review evidence on how three independent psychological constructs may contribute to UE: heightened food reward sensitivity, lower self-control, and higher negative affect. UE mediates all three constructs’ associations with BMI and food intake. Finally, we review and meta-analyse brain systems subserving UE: namely, (i) the dopamine mesolimbic circuit associated with reward sensitivity, (ii) frontal cognitive networks sustaining dietary self-control, and (iii) the hypothalamus-pituitary-adrenal axis, amygdala and hippocampus supporting stress reactivity. While there are limits to the explanatory and predictive power of the UE phenotype, we conclude that treating different eating-related constructs as a single concept, UE, enables drawing robust conclusions on the relationship between food intake and BMI, psychological variables, and brain structure and function. [mehr]

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Aus unserer Umwelt nehmen wir ständig Informationen auf, die eingeordnet und bewertet werden müssen, damit in unserem Bewusstsein ein individuell kohärentes Bild erschaffen werden kann. Eine Reihe empirischer Befunde in den letzten Jahren hat Hinweise erbracht, die darauf hindeuten, dass der funktionelle Zustand des Gehirns diese Informationsverarbeitung beeinflusst. So konnte beispielsweise gezeigt werden, dass die Amplitude und Phase kortikaler Aktivität, sowie die Kommunikation zwischen kortikalen Arealen relevant sind für die Verarbeitung unisensorischer und multisensorischer Reize. In diesem Vortrag werde ich die aktuelle Literatur zu den neuronalen Mechanismen multisensorischer Verarbeitung zusammenfassen und dabei vor Allem auf neuronale Oszillationen eingehen. Dabei schlage ich vor, dass unterschiedliche Frequenzbänder ergänzende Mechanismen multisensorischer Verarbeitung abbilden. Im Anschluss werde ich offene Fragen in diesem Forschungsfeld diskutieren, mit einem besonderen Augenmerk auf der Rolle kognitiver Prozesse, Aufmerksamkeit, Erwartungen und Emotionen. [mehr]

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The identification of biomarkers. which can help predict disease outcome. remains one of the most promising research areas across a variety of diseases. Particularly. studying the spatial distribution of underlying disease burden may provide important insights into pathological patterns. Stroke is one of the leading causes of death and disability worldwide. however. it remains largely understudied in the acute setting due to time restrictions during data acquisition and the resulting low resolution magnetic resonance images. This has made outcome prediction particularly difficult. as it leads to heterogeneity in the data and/or methodologies between studies. One of the key phenotypes of stroke research is a patient's white matter hyperintensity (WMH) burden. most commonly assessed using FLAIR images. which has been linked to stroke outcome. Studies often rely on measuring the total burden and summarize it as a single number: it’s volume. based on manual outlines on a patient’s scan. The lack of an automated segmentation methodology for clinical data has so far hindered large-scale. reproducible investigations. In the first part of this talk. we present an automated pipeline for monomodal automatic WMH segmentation. which can alleviate some of these challenges. Specifically. we demonstrate it's efficacy for volume estimation in a cohort of 2.533 patients. showing the association between higher WMH burden and poorer outcome after stroke (p<0.001). In the second half of this talk. we demonstrate the use of WMH segmentations for investigating spatial WMH disease burden and how other clinical variables can modify these patterns. In particular. we demonstrate effects for hypertension and smoking status. and show that these clinical variables lead to a shift of disease burden from posterior to anterior vascular regions (p<0.05 and p<0.01. respectively). This illustrates the potential of uncovering spatial variations of disease patterns by using large-scale cohorts. [mehr]

Despite the thorough mapping of brain pathways involved in eating behavior, no treatment aimed at modulating eating dysregulation has been established yet. Aiming for a feasible brain-modulation tool, we evaluated N.I.R. H.E.G. (Near Infra-Red Hemoencephalography) neurofeedback training on appetite control, weight and food-related brain activity. Following the intervention, we observed trends of increased self-control related to food, weight reduction and increased activation of sOFC during a response-inhibition fMRI task. N.I.R. H.E.G. holds a promising potential as a feasible neurofeedback platform for modulation of cortical brain circuits involved in self-control and eating behavior. This is an invitation for further evaluation and development of N.I.R. H.E.G. as a brain modifying device for the treatment and prevention of obesity. Based on: A pilot study of a novel therapeutic approach to obesity: CNS modification by N.I.R. H.E.G. neurofeedback Clin Nutr. 2018 Feb 7. pii: S0261-5614(18)30043-8. Percik R, Cina J, Even B, Gitler A, Geva D, Seluk L, Livny A [mehr]

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The dopaminergic circuits lie at the core of learning and motivational processes through which we are able to form predictions about the future and take action accordingly. Studies in animals have shown that midbrain dopaminergic neurons projecting to the striatum signal events in the environment that deviate from what we expect. A prevalent model of the dopaminergic function suggests that these so-called prediction errors –propagated by the D1 dopamine receptors to cortical areas – modulate synaptic plasticity and thereby facilitate learning and initiation of action. While D2 dopamine receptors in the striatum as well as prefrontal striatal projection regulate and modulate this signal propagation. How this neurobiological model of dopaminergic activity relates to behaviour has been difficult to address. In my talk I will present several pharmacogenetic studies that map manipulations of the dopaminergic system on to various computational phenotypes. First of all, we are interested in the role of dopamine in updating beliefs in a social as well as a non-social context. And second, we explored dopamine’s involvement in model-based decision making. Specifically, how does blocking D2 transmission affect our ability to keep the regularities and knowledge about the world online as we make decisions and learn about the states of the world that are not directly observed? [mehr]

What drives us to trust someone we just met? Did we eat spaghetti for lunch because we saw our colleague eat spaghetti? Can we become happier when we are nicer to our neighbors? How does the content of our breakfast have anything to do with our social interactions throughout the day? Research from different disciplines such as economics, psychology and neuroscience have attempted to investigate the motives and modulators of human decision making. Our decisions can be flexibly modulated by the different experiences we have in our daily lives. These modulations can occur through our social networks, through the impact of our own behavior on the social environment, but also simply by the food we have eaten. Here, I will present a series of recent studies from my lab in which we shed light on the psychological, neural and metabolic motives and modulators of human decision making. [mehr]

Recent studies have questioned the reliability of many functional neuroimaging findings reported in the literature over the past decades. In my talk I will illustrate how novel analytic workflows (Dukart et al., 2018, Scientific Reports; Holiga et al. 2019, Science Translational Medicine) may overcome some of the critical limitations of functional neuroimaging analyses improving the reliability of the methods as well as providing an improved interpretation of potential signals with respect to underlying biology and for identification of biomarkers for neurological and psychiatric diseases. [mehr]

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Various psychological disorders are characterized by pronounced cognitive biases, including biased orienting of attention to certain stimuli, distorted expectation of the likelihood to encounter specific objects, biased interpretation of ambiguous information and biased perception. Although these biases are common in psychopathology, most of the studies so far focused on one bias by employing traditional analysis methods. Therefore, little is known about the correlational and causal relations between different biases and about combined patterns that may characterize certain disorders. In this talk, I will discuss recent behavioral, fMRI and autonomic data showing links between biases, as well as modulation of biased emotional processing in different populations. Moreover, by employing machine-learning based analysis, we managed to specify specific behavioral patterns that characterize anxiety vs. depression, two disorders that share many characteristics and show high comorbidity. Finally, I will discuss recent evidence for abnormalities in the blood pressure reaction to aversive pictures among individuals with pre- hypertension, a population that is usually not studied in the context of psychological reactions. Taken together, these findings suggest new strategies to explore and treat maladaptive behaviors that have fundamental implications on the patients’ life. [mehr]

A considerable body of work over the last 10 years combining non-invasive electrophysiology (electroencephalography/magnetoencephalography) in patient populations with preclinical research has contributed to the conceptualization of schizophrenia as a disorder associated with aberrant neural dynamics and disturbances in excitation/inhibition (E/I) balance parameters. Specifically, I will propose that recent technological and analytic advances in MEG provide novel opportunities to address these fundamental questions as well as establish important links with translational research. We have carried out several studies which have tested the importance of neural oscillations in the pathophysiology of schizophrenia through a combination of MEG-measurements in ScZ-patients and pharmacological manipulations in healthy volunteers which target the NMDA-receptor. These results highlight a pronounced impairment in high-frequency activity in both chronic and unmedicated patients which could provide novel insights into basic circuit mechanisms underlying cognitive and perceptual dysfunctions. However, acute Ketamine only partly recreates abnormalities observed in both resting-state and task-related neural oscillations in ScZ, suggesting potentially shortcoming of this pharmacological model for capturing large-scale network dysfunctions. Our recent work has employed MEG to develop a biomarker for early detection and diagnosis of ScZ. We have obtained MEG- and MRS-data from 125 participants meeting clinical high-risk criteria (CHR), 90 controls and 30 FEP-patients. We found marked changes in the synchrony of gamma-band oscillations in visual and auditory cortices during sensory processing which predicted clinical outcomes. In addition, CHR-participants were characterized by elevated broad-band gamma-band activity at rest which correlated with increased glutamate levels. Together, these findings highlight the potential of MEG-based biomarkers for the early diagnosis of ScZ in at-risk populations. [mehr]

Exposure to childhood adversity is common and associated with a host of negative developmental outcomes as well as differences in neural structure and function. It is commonly posited that these social experiences “get under the skin” in early childhood, increasing long-term risk through disruptions to biology. In this talk I propose a novel approach to studying the link between adversity, brain development, and risk for psychopathology, the dimensional model of adversity and psychopathology (DMAP). In this model we propose that adversity exposure can be defined according to different dimensions which we expect to impact health and well-being through different neural substrates. Whereas we expect deprivation to primarily disrupt function and structure of lateral association cortex (e.g., dorsolateral prefrontal cortex and superior parietal cortex) and thus complex cognitive processing such as executive functioning. In contrast, we expect threat to alter structure and function of subcortical structures such as the hippocampus and amygdala and midline regions associated with emotion regulation such as the ventral medial prefrontal cortex and thus, associated emotion reactivity and automatic regulation processes. In a series of studies I test the basic tenants of the DMAP concluding that initial evidence, using both a priori hypothesis testing and data-driven approaches is consistent with the proposed model. I conclude by describing future work addressing multiple dimensions of adversity and potential adjustments to the model. [mehr]

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